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DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development

Lookup NU author(s): Dr Richard Quinton


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© The Author 2017. Congenital hypogonadotropic hypogonadism(CHH) is a rare genetic disease characterized by absent puberty and infertility due to GnRH deficiency, and is often associated with anosmia [Kallmann syndrome (KS)]. The genetic etiology of CHH is heterogeneous, andmore than 30 genes have been implicated in approximately 50% of patients with CHH.We hypothesized that genes encoding axon-guidance proteins containing fibronectin type-III (FN3) domains (similar to ANOS1, the first gene associated with KS), aremutated in CHH.We performed whole-exome sequencing in a cohort of 133 CHH probands to test this hypothesis, and identified rare sequence variants (RSVs) in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). In vitro studies of these RSVs revealed altered intracellular signaling associated with defects in cellmorphology, and confirmed five heterozygous DCCmutations in 6 probands-5 of which presented as KS. Two KS probands carry heterozygousmutations in both DCC and NTN1 consistent with oligogenic inheritance. Further, we show that Netrin-1 promotesmigration in immortalized GnRH neurons (GN11 cells). This study implicates DCC and NTN1 mutations in the pathophysiology of CHH consistent with the role of these two genes in the ontogeny of GnRH neurons inmice.

Publication metadata

Author(s): Bouilly J, Messina A, Papadakis G, Cassatella D, Xu C, Acierno JS, Tata B, Sykiotis G, Santini S, Sidis Y, Elowe-Gruau E, Phan-Hug F, Hauschild M, Bouloux P-M, Quinton R, Lang-Muritano M, Favre L, Marino L, Giacobini P, Dwyer AA, Niederlander NJ, Pitteloud N

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2018

Volume: 27

Issue: 2

Pages: 359-372

Print publication date: 15/01/2018

Online publication date: 30/11/2017

Acceptance date: 16/11/2017

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddx408


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